Numerous chromium-containing compositions are well known in the art, however, all or almost all of them suffer from one or more disadvantages. Most significantly, while some of the chromium-containing supplements are embroiled in toxicity issues (e.g., Cr-picolinate), others have only relatively low solubility and/or bioavailability (e.g., chromium yeast), or are expensive (e.g., chromium lactoferrin) in their production.
For example, WO 03/101436 and U.S. Pat. No. 3,925,433 describe various alpha amino acid complexes with Cr3+ in nutritional supplements. Similarly, pure alpha amino acid chromium complexes are taught in US 2003/0228394 as animal feed additive. To increase bioavailability of chromium from amino acid complexes, histidine or threonine may be employed as main ligand as reported in U.S. Pat. Nos. 6,689,383, and 6,548,687, respectively. Where desirable, non-proteinogenic amino acid complexes with chromium may be prepared as disclosed in U.S. Pat. No. 6,071,545 and US 2004/0106591. Amino acid containing mixed complexes are taught in WO 02/056889, where an amino acid and nicotinic acid act as ligands. While amino acid ligands are typically considered nutritionally safe, amino acid complexes formed with chromium tend to pose several drawbacks. Among other things, bioavailability of the chromium from the complex is often relatively low. Furthermore, at least some of such complexes have displayed toxicity to some degree.
To overcome at least some of the problems associated with amino acid complexes, non-amino acid ligands (e.g., nicotinate and picolinic acid) are relatively common and often exhibit improved bioavailability, and may further be employed in mixed complexes and/or combination formulations. For example, known non-amino acid chromium complexes include polynicotinate chromium complexes as described in U.S. Pat. No. 6,323,192. Similarly, complexes in which niacin binds chromium were reported as reducing blood glucose in US 2003/0133992. In yet another example, chromium arginate or chromium chalidamate were used as defined and water soluble chromium complexes that were administered in combination with an oxygen uptake enhancer as described in US 2004/00053688. Still further known preparations include those in which Cr-picolinate or Cr-polynicotinate are combined with a cyclooxygenase inhibitor as described in U.S. Pat. No. 6,713,469, or with conjugated linoleic acid or conjugated linoleic alcohol as taught in U.S. Pat. No. 6,809,115.
Other isolated and defined chromium ligands include sucrose as taught in U.S. Pat. No. 3,914,410, acetylacetonate as taught in U.S. Pat. No. 4,571,391, short chain carboxylic acids as described in U.S. Pat. No. 5,846,581 and U.S. Pat. No. 6,303,158, or selected synthetic peptide-like ligands as described in U.S. Pat. No. 5,266,560. Similarly, chromium carnitine complexes in combination with vanadyl sulfate, lipoic acid and other ingredients were reported in U.S. Pat. No. 6,733,793, while EP 0 037 144 describes a negatively charged C3-type ligand (e.g., optionally substituted malonaldehyde complexes). In U.S. Pat. No. 6,149,948, a complex of the formula [Cr3O(O2CCH2CH3)6(H2O)3]+ is used as a chromium carrier. While such defined complexes tend to overcome at least some of the difficulties associated with amino acid ligands, toxicity issues frequently remain, particularly at relatively high dosages, and/or where the compounds are administered over a relatively long period.
Toxicity may be reduced to at least some degree where specific naturally occurring ligands are selected. For example, isolated bovine chromium-binding protein (e.g., Biochemistry. 1996 Oct. 1; 35(39):12963-9, or Eur J. Biochem. 1987 Jun. 15; 165(3):627-31) was described as a source of chromium supplementation as taught in U.S. Pat. No. 5,872,102. Similarly, lactoferrin was reported as a chromium ligand in U.S. Pat. No. 6,379,693, and in yet another example (see e.g., WO 04/022083), proteolysis-derived low-molecular weight peptides are employed as ligands, that preferably have a proline terminus. Alternatively, oxidized leather scrap hydrolysate from leather tanning refuse was reported as a carrier for chromium in the preparation of animal feed as reported in U.S. Pat. No. 6,352,714. While many hydrolyzed protein preparations are often low- or even non-toxic, various difficulties nevertheless remain. Among other problems, crude hydrolysate generally has an off-taste that is hard to mask, and where the hydrolysate is purified or otherwise processed, production costs often significantly increase. Still further, the use of hydrolytic enzymes may pose a health concern where the enzymes are not properly inactivated.
In yet another known approach of preparing chromium-containing supplements, yeast is cultivated in a medium that includes a chromium source, which provides the chromium to the yeast cell that is subsequently harvested, pasteurized, and optionally dried and/or pulverized. Such products are typically known as chromium yeast products. For example, a common preparation of a chromium yeast product is described in U.S. Pat. Nos. 4,348,483 and 4,343,905 in which the yeast is incubated with a non-toxic chromium compound to form a chromium-enriched yeast cell preparation. The so fermented yeast is then isolated and/or powderized to provide the chromium supplement. To improve the chromium content, selected yeast strains for cultivation of yeast in a metal-containing medium are described in U.S. Pat. No. 6,140,107. Alternatively, or additionally, mixed amino acid nicotinate chromium complexes can be used in the fermentation medium to boost the chromium content of a yeast as described in U.S. Pat. No. 6,248,323. While such preparations are often well tolerated, the low solubility of the chromium yeast product frequently poses a significant hurdle to incorporate such products into a food or beverage. Moreover, and at least in part due to the relatively poor solubility, bioavailability of chromium from such yeast products is typically low.
Yeast has also been used as starting material to purify defined and metabolically active substances as described in U.S. Pat. No. 6,261,606. Similarly, EP 0 248 057 describes isolation of a glucose tolerance factor from yeast. Surprisingly, such isolated factor was free of chromium and was identified as a quinoline compound. However, isolation of such substances is typically labor intensive and therefore often not economic.
Thus, while there are numerous chromium complexes known in the art, toxicity, low bioavailability, and/or low water solubility limit the usefulness of these complexes. Therefore, there is a constant need to find new chromium compounds/complexes that have higher biological activity/bioavailability, higher safety/less toxicity, sufficient chemical stability and high water solubility.